US4012373A - Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones - Google Patents

Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones Download PDF

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Publication number
US4012373A
US4012373A US05/291,503 US29150372A US4012373A US 4012373 A US4012373 A US 4012373A US 29150372 A US29150372 A US 29150372A US 4012373 A US4012373 A US 4012373A
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United States
Prior art keywords
sub
lower alkyl
hydrogen
ethyl
compound
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Expired - Lifetime
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US05/291,503
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English (en)
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Theodor Denzel
Hans Hoehn
Ernst Schulze
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Priority to US05/291,503 priority Critical patent/US4012373A/en
Priority to CA178,721A priority patent/CA1013349A/en
Priority to GB3932573A priority patent/GB1450452A/en
Priority to DE19732346466 priority patent/DE2346466A1/de
Priority to FR7333998A priority patent/FR2200003B1/fr
Priority to JP48107409A priority patent/JPS4969700A/ja
Application granted granted Critical
Publication of US4012373A publication Critical patent/US4012373A/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • This invention relates to new pyrazolo[',4'-2,3]-pyrido [4,5-e]b-benzo-1,5-diazepinones. These new compounds have the general formula ##STR2##
  • R 1 represents hydrogen, lower alkyl, phenyl, phenyl-lower alkyl or cyclo-lower alkyl
  • R 2 represents hydrogen, lower alkyl or phenyl
  • R 3 and R 8 each represents hydrogen, alkyl up to 10 carbons, preferably lower alkyl, phenyl-lower alkyl, cyclo-lower alkyl or an amino-alkylene group of the formula II ##STR3## in which R 10 , R 11 each is hydrogen, lower alkyl or hydroxy-lower alkyl.
  • the nitrogen may be part of a heterocyclic of 5 or 6-members, in which an additional nitrogen, sulfur or oxygen is present, i.e., pyrrolidino, piperidino, morpholino or thiamorpholino.
  • These heterocyclic groups may also bear a lower alkyl, lower alkoxy or hydroxy-lower alkyl group, for example 2,3 or 4-(lower alkoxy)piperidino, e.g., 2-methoxypiperidino, 2,3- or 4-(lower alkyl)piperidino, e.g., 2,3-or 4-methylpiperidino, (lower alkyl)pyrrolidino, e.g., 2-methylpyrrolidino, (lower alkoxy)pyrrolidino, e.g., 2-ethoxypyrrolidino (lower alkyl)morpholino, e.g., 3-methylmorpholino or 2-methylmorpholino, (lower alkoxy)morpholino,
  • R 4 , R 5 , R 6 and R 7 each is hydrogen, halogen, lower alkyl or lower alkoxy.
  • R 9 is hydrogen, lower alkyl or phenyl.
  • Preferred compounds of formula I are those wherein R 1 is hydrogen or lower alkyl, especially ethyl, R 2 is hydrogen or methyl, R 3 and R 8 each is hydrogen, lower alkyl or di(lower alkyl)amino-lower alkylene, especially ethyl- or dimethylaminopropyl, R 4 , R 5 , R 6 , R 7 are hydrogen, halogen, especially chlorine, or lower alkoxy, especially methoxy, R 9 is hydrogen or lower alkyl, especially hydrogen.
  • the various groups referred to above are of the following types: the lower alkyl and lower alkylene groups include straight or branched chain hydrocarbon groups of up to seven carbon atoms, like methyl, ethyl, propyl, isopropyl and the like, up to four carbon atom chains being preferred.
  • the phenyl-lower alkyl and alkoxy contain similar radicals attached to a phenyl or oxygen, respectively. All four common halogens are included but chlorine and bromine are preferred.
  • the cyclo-lower alkyl groups are the 3 to 6 carbon alicyclics cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, especially the last two.
  • a 5-aminopyrazole of the formula ##STR4## [produced analogous to the procedure described in Z.f. Chemie 10, 386 (1970)] is made to react with a compound of the formula ##STR5## by heating at a temperature of about 120°-130° C.
  • the resulting compound of the formula ##STR6## is cyclized in an inert organic solvent such as diphenyl ether at about 230° to about 260° C. while distilling off the alcohol formed, producing a compound of the formula ##STR7## in which R 1 , besides the alkyl groups, represents also the above mentioned groups.
  • This 4-hydroxy compound is refluxed for several hours with a phosphorus halide like phosphorus oxychloride to obtain the intermediate of the formula ##STR8##
  • This compound of formula VII is made to react with an appropriately substituted 2-nitroaniline in the presence of a base like sodium hydride, in a high boiling solvent like dioxane or diethyleneglycoldimethylether to produce a compound of the formula ##STR9##
  • the cyclization may also be effected by heating compounds of formula IX with a strong acid like polyphosphoric acid.
  • a compound of formula IX is treated with an inorganic base like sodium hydroxide resulting in a compound of the formula ##STR11## which is cyclized to the compound of formula I by reacting with an inorganic acid chloride like thionyl chloride, phosphorus trichloride or the like.
  • the compound of formula VI may be treated with an alkylating agent, e.g., an alkyl halide like ethyl iodide, to form an intermediate of the formula ##STR12##
  • an alkylating agent e.g., an alkyl halide like ethyl iodide
  • Saponification of the product of formula XI e.g., with a conventional base, for example an alkali metal hydroxide, like potassium hydroxide or sodium hydroxide, produces a compound of the formula ##STR13##
  • This acid is transformed to a product of the formula ##STR14## by treatment with an inorganic acid chloride like thionyl chloride.
  • the compound of formula I is now produced by heating the compound of formula XV in a solvent like diethyleneglycol dimethyl ether, dimethylformamide or the like at a temperature of about 140°-160°.
  • a product of formula I wherein R 1 is hydrogen is produced by a modification of the foregoing procedure.
  • a 5-aminopyrazole of formula II is used, wherein R 1 is an arylmethyl- or a heteromethyl group.
  • This starting material has the formula ##STR17## wherein R 12 is an aromatic or heterocyclic nucleus like phenyl, naphthyl, furyl, pyridyl, pyrimidyl, pyrazinyl or the like.
  • This material is processed as described above through the reaction with a compound of formula IV and cyclization of the product corresponding to formula V to obtain a compound of formula VI.
  • the compound of formula VI having the --CH 2 --R 12 substituent in the 1-position, is oxidized with an oxidizing agent like selenium dioxide in a high boiling solvent like diethyleneglycol dimethylether at about 160° C.
  • an oxidizing agent like selenium dioxide in a high boiling solvent like diethyleneglycol dimethylether at about 160° C.
  • R 1 is hydrogen.
  • this intermediate is converted to the chlorine compound of formula VII by means of phosphorus oxychloride which is processed as described above.
  • the basic members of the group of formula I form salts which are also part of this invention.
  • the salts include acid addition salts and quaternary ammonium salts, particularly the non-toxic, physiologically acceptable members.
  • the bases of formula I form salts by reaction with a variety of inorganic and organic acids providing acid addition salts including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, malate, citrate, acetate, ascorbate, succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate and toluenesulfonate.
  • hydrohalides especially hydrochloride and hydrobromide
  • sulfate nitrate, borate, phosphate, oxalate, tartrate, malate, citrate, acetate, ascorbate, succinate, benzenesul
  • the acid addition salts frequently provide a means for isolating the product, e.g., by forming and precipitating the salt in an appropriate menstruum in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of formula I.
  • a base such as barium hydroxide or sodium hydroxide
  • Other salts may then be formed from the free base by reaction with an equivalent of acid.
  • Quaternary ammonium salts include, for example, the lower alkyl halides and sulfates (e.g., methyl bromide and diethyl sulfate) and the phenyl-(lower alkyl) halides, sulfates and sulfonates (e.g., benzyl chloride, benzyl sulfate, benzenesulfonate and the like, which are formed by a conventional quaternization reaction.
  • the lower alkyl halides and sulfates e.g., methyl bromide and diethyl sulfate
  • phenyl-(lower alkyl) halides, sulfates and sulfonates e.g., benzyl chloride, benzyl sulfate, benzenesulfonate and the like, which are formed by a conventional quaternization reaction.
  • the new compounds of this invention are central nervous system depressants and may be used as tranquilizers or ataractic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species, in the same manner as chlordiazepoxide.
  • a compound or mixture of compounds of formula I, or non-toxic, physiologically acceptable acid addition or quaternary ammonium salt thereof may be administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like.
  • These may be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg. per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.
  • the new compounds also increase the intracellular concentration of adenosine-3',5'-cyclic monophosphate, and thus by the administration of about 1 to 50 mg/kg/day, preferably about 10 to 50 mg/kg, in single or two to four divided doses in conventional oral or parenteral dosage forms such as those described above may be used to alleviate the symptoms of asthma.
  • the new compounds of this invention have anti-inflammatory properties and are useful as anti-inflammatory agents, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mammalian species such as rats, dogs and the like when given orally in dosages of about 15 to 50 mg/kg/day, preferably 15 to 25 mg/kg/day, in single or 2 to 4 divided doses, as indicated by the carageenan edema assay in rats.
  • the active substance may be utilized in compositions such as tablets, capsules, solutions or suspensions containing up to about 300 mg. per unit of dosage of a compound or mixture of compounds of formula I or physiologically acceptable acid addition or quaternary ammonium salt thereof.
  • Topical preparations containing about 0.1 to 3 percent by weight of active substance in a lotion, salve or cream may also be used.
  • the compound is recrystallized from N-hexane, m.p. 55°-57°.
  • the hydrochloride salt is formed by treating the above product with dilute ethanolic hydrogen chloride solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US05/291,503 1972-09-22 1972-09-22 Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones Expired - Lifetime US4012373A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US05/291,503 US4012373A (en) 1972-09-22 1972-09-22 Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones
CA178,721A CA1013349A (en) 1972-09-22 1973-08-13 Derivatives of pyrazolo(3',4',-2,3)pyrido(4,5-e) b-benzo-1,5-diazepinoes
GB3932573A GB1450452A (en) 1972-09-22 1973-08-20 Derivatives of pyrazolo 3,4-2,3- pyrido 4,5-e- b-benzo-1,5- diazepinones
DE19732346466 DE2346466A1 (de) 1972-09-22 1973-09-08 Neue pyrazolopyridobenzodiazepinone mit ihren salzen
FR7333998A FR2200003B1 (US07321065-20080122-C00020.png) 1972-09-22 1973-09-21
JP48107409A JPS4969700A (US07321065-20080122-C00020.png) 1972-09-22 1973-09-22

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US05/291,503 US4012373A (en) 1972-09-22 1972-09-22 Pyrazolo[3',4'-2,3]pyrido[4,5-e]b-benzo-1,5-diazepinones

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US (1) US4012373A (US07321065-20080122-C00020.png)
JP (1) JPS4969700A (US07321065-20080122-C00020.png)
CA (1) CA1013349A (US07321065-20080122-C00020.png)
DE (1) DE2346466A1 (US07321065-20080122-C00020.png)
FR (1) FR2200003B1 (US07321065-20080122-C00020.png)
GB (1) GB1450452A (US07321065-20080122-C00020.png)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060089375A1 (en) * 2002-09-16 2006-04-27 Allen David G Pyrazolo[3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors
WO2010003025A1 (en) * 2008-07-01 2010-01-07 Genentech, Inc. Bicyclic heterocycles as mek kinase inhibitors
US20110124622A1 (en) * 2008-07-01 2011-05-26 Genentech, Inc. Isoindolones derivatives as mek kinase inhibitors and methods of use
WO2011041989A3 (es) * 2009-10-09 2011-09-15 Centro de Investigación y Desarrollo de Medicamentos (CIDEM) Sistemas tricíclicos y tetracíclicos con actividad sobre el sistema nervioso central y vascular
US10272074B2 (en) * 2015-01-29 2019-04-30 Sanford Burnham Prebys Medical Discovery Institute Inhibitors of glucocorticoid receptor translocation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58164628A (ja) * 1982-09-28 1983-09-29 Mitsuboshi Belting Ltd 超高分子量ポリエチレン焼結体の製造方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3420818A (en) * 1964-08-07 1969-01-07 Sandoz Ag Tetrahydroisoquinolines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3420818A (en) * 1964-08-07 1969-01-07 Sandoz Ag Tetrahydroisoquinolines

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060089375A1 (en) * 2002-09-16 2006-04-27 Allen David G Pyrazolo[3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors
WO2010003025A1 (en) * 2008-07-01 2010-01-07 Genentech, Inc. Bicyclic heterocycles as mek kinase inhibitors
US20110124622A1 (en) * 2008-07-01 2011-05-26 Genentech, Inc. Isoindolones derivatives as mek kinase inhibitors and methods of use
US20110190257A1 (en) * 2008-07-01 2011-08-04 Genetech, Inc. Bicyclic heterocycles as mek kinase inhibitors
JP2011526926A (ja) * 2008-07-01 2011-10-20 ジェネンテック， インコーポレイテッド 置換二環式ヘテロ環化合物と使用方法
US8492427B2 (en) 2008-07-01 2013-07-23 Genentech, Inc. Isoindolones derivatives as MEK kinase inhibitors and methods of use
AU2009266956B2 (en) * 2008-07-01 2014-03-20 Genentech, Inc. Bicyclic heterocycles as MEK kinase inhibitors
US8841462B2 (en) 2008-07-01 2014-09-23 Robert A. Heald Bicyclic heterocycles as MEK kinase inhibitors
WO2011041989A3 (es) * 2009-10-09 2011-09-15 Centro de Investigación y Desarrollo de Medicamentos (CIDEM) Sistemas tricíclicos y tetracíclicos con actividad sobre el sistema nervioso central y vascular
US9315497B2 (en) 2009-10-09 2016-04-19 Centro de Investigacion Y Desarrollo de . . . (CIDEM) Laboratorio de Sintesis Organica de La Facultad . . . Tricyclic and tetracyclic systems with activity on the central nervous and vascular systems
US10138231B2 (en) 2009-10-09 2018-11-27 Centro de Investigacion Y Desarrollo de... (CIDEM) Tricyclic and tetracyclic systems acting upon the vascular and central nervous systems
US10272074B2 (en) * 2015-01-29 2019-04-30 Sanford Burnham Prebys Medical Discovery Institute Inhibitors of glucocorticoid receptor translocation

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CA1013349A (en) 1977-07-05
DE2346466A1 (de) 1974-04-11
JPS4969700A (US07321065-20080122-C00020.png) 1974-07-05
GB1450452A (en) 1976-09-22
FR2200003B1 (US07321065-20080122-C00020.png) 1977-03-11
FR2200003A1 (US07321065-20080122-C00020.png) 1974-04-19

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